tbuckley/cabot-search huggingface dataset:
Discovery of a novel dual-targeting D-peptide to block CD24/Siglec-10 and PD-1/PD-L1 interaction and synergize with radiotherapy for cancer immunotherapy
Authors: Wenhui Shen, Peishang Shi, Qingyu Dong, Xiuman Zhou, Chunxia Chen, Xinghua Sui, Wentong Tian, Xueqin Zhu, Xiaoxi Wang, Shengzhe Jin, Yahong Wu, Guanyu Chen, Lu Qiu, Wenjie Zhai, Yanfeng Gao
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Aside from immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1), intervention of CD47/Sirpα mediated ‘don’t eat me’ signal between macrophage and tumor cell is considered as a promising therapeutic approach for cancer immunotherapy. Compared with CD47, the novel immune checkpoint CD24/Siglec-10 can also deliver ‘don’t eat me’ signal and CD24 shows much lower expression level in normal tissue which might avoid unwanted side effects. Methods Cell-based phage display biopanning and D-amino acid modification strategy were used to identify the CD24/Siglec-10 blocking peptide. Cell-based blocking assay and microscale thermophoresis assay were used to validate the blocking and binding activities of the peptide. Phagocytosis and co-culture assays were used to explore the in vitro function of the peptide. Flow cytometry was performed to assess the immune microenvironment after the peptide treatment in vivo. Results A CD24/Siglec-10 blocking peptide (CSBP) with hydrolysis-resistant property was identified. Surprisingly, we found that CSBP could not only block the interaction of CD24/Siglec-10 but also PD-1/PD-L1. CSBP could induce the phagocytosis of tumor cell by both the macrophages and monocytic myeloid-derived suppressor cells (M-MDSCs), which can further activate CD8 + T cells. Besides, combination of radiotherapy and CSBP synergistically reduced tumor growth and altered the tumor microenvironment in both anti-PD-1-responsive MC38 and anti-PD-1-resistant 4T1 tumor models. Conclusions In summary, this is the first CD24/Siglec-10 blocking peptide which blocked PD-1/PD-L1 interaction as well, functioned via enhancing the phagocytosis of tumor cells by macrophages and M-MDSCs, and elevating the activity of CD8 + T cells for cancer immunotherapy.
Whole genome sequencing across clinical trials identifies rare coding variants in GPR68 associated with chemotherapy-induced peripheral neuropathy
Authors: Zia Khan, Min Jung, Megan Crow, Rajat Mohindra, Vidya Maiya, Joshua S. Kaminker, David H. Hackos, G. Scott Chandler, Mark I. McCarthy, Tushar Bhangale
Journal: Genome Medicine (2023)

Abstract Background Dose-limiting toxicities significantly impact the benefit/risk profile of many drugs. Whole genome sequencing (WGS) in patients receiving drugs with dose-limiting toxicities can identify therapeutic hypotheses to prevent these toxicities. Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting neurological toxicity of chemotherapies with no effective approach for prevention. Methods We conducted a genetic study of time-to-first peripheral neuropathy event using 30× germline WGS data from whole blood samples from 4900 European-ancestry cancer patients in 14 randomized controlled trials. A substantial number of patients in these trials received taxane and platinum-based chemotherapies as part of their treatment regimen, either standard of care or in combination with the PD-L1 inhibitor atezolizumab. The trials spanned several cancers including renal cell carcinoma, triple negative breast cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, ovarian cancer, and melanoma. Results We identified a locus consisting of low-frequency variants in intron 13 of GRID2 associated with time-to-onset of first peripheral neuropathy (PN) indexed by rs17020773 ( p = 2.03 × 10 −8 , all patients, p = 6.36 × 10 −9 , taxane treated). Gene-level burden analysis identified rare coding variants associated with increased PN risk in the C-terminus of GPR68 ( p = 1.59 × 10 −6 , all patients, p = 3.47 × 10 −8 , taxane treated), a pH-sensitive G-protein coupled receptor (GPCR). The variants driving this signal were found to alter predicted arrestin binding motifs in the C-terminus of GPR68 . Analysis of snRNA-seq from human dorsal root ganglia (DRG) indicated that expression of GPR68 was highest in mechano-thermo-sensitive nociceptors. Conclusions Our genetic study provides insight into the impact of low-frequency and rare coding genetic variation on PN risk and suggests that further study of GPR68 in sensory neurons may yield a therapeutic hypothesis for prevention of CIPN.
Integrating genetics and metabolomics from multi-ethnic and multi-fluid data reveals putative mechanisms for age-related macular degeneration
Authors: Xikun Han, Ines Lains, Jun Li, Jinglun Li, Yiheng Chen, Bing Yu, Qibin Qi, Eric Boerwinkle, Robert Kaplan, Bharat Thyagarajan, Martha Daviglus, Charlotte E. Joslin, Jianwen Cai, Marta Guasch-Ferré, Deirdre K. Tobias, Eric Rimm, Alberto Ascherio, Karen Costenbader, Elizabeth Karlson, Lorelei Mucci, A. Heather Eliassen, Oana Zeleznik, John Miller, Demetrios G. Vavvas, Ivana K. Kim, Rufino Silva, Joan Miller, Frank Hu, Walter Willett, Jessica Lasky-Su, Peter Kraft, J. Brent Richards, Stuart MacGregor, Deeba Husain, Liming Liang
Journal: Cell Reports Medicine (2023)

Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. Investigating shared genetic components between metabolites and AMD can enhance our understanding of its pathogenesis. We conduct metabolite genome-wide association studies (mGWASs) using multi-ethnic genetic and metabolomic data from up to 28,000 participants. With bidirectional Mendelian randomization analysis involving 16,144 advanced AMD cases and 17,832 controls, we identify 108 putatively causal relationships between plasma metabolites and advanced AMD. These metabolites are enriched in glycerophospholipid metabolism, lysophospholipid, triradylcglycerol, and long chain polyunsaturated fatty acid pathways. Bayesian genetic colocalization analysis and a customized metabolome-wide association approach prioritize putative causal AMD-associated metabolites. We find limited evidence linking urine metabolites to AMD risk. Our study emphasizes the contribution of plasma metabolites, particularly lipid-related pathways and genes, to AMD risk and uncovers numerous putative causal associations between metabolites and AMD risk.
New hormone receptor-positive breast cancer mouse cell line mimicking the immune microenvironment of anti-PD-1 resistant mammary carcinoma
Authors: Maria Perez-Lanzon, Vincent Carbonnier, Pierre Cordier, Fatima Domenica Elisa De Palma, Adriana Petrazzuolo, Christophe Klein, Floriane Arbaretaz, Khady Mangane, Gautier Stoll, Isabelle Martins, Helene Fohrer Ting, Juliette Paillet, Sophie Mouillet-Richard, Delphine Le Corre, Wenjjin Xiao, Marine Sroussi, Chantal Desdouets, Pierre Laurent-Puig, Jonathan Pol, Carlos Lopez-Otin, Maria Chiara Maiuri, Guido Kroemer
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Progress in breast cancer (BC) research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best studied mouse strain, C57BL/6, is also the only one for which multiple genetic variants are available to facilitate the exploration of the cancer-immunity dialog. Driven by the fact that no hormone receptor-positive (HR + ) C57BL/6-derived mammary carcinoma cell lines are available, we decided to establish such cell lines. Methods BC was induced in female C57BL/6 mice using a synthetic progesterone analog (medroxyprogesterone acetate, MPA) combined with a DNA damaging agent (7,12-dimethylbenz[a]anthracene, DMBA). Cell lines were established from these tumors and selected for dual (estrogen+progesterone) receptor positivity, as well as transplantability into C57BL/6 immunocompetent females. Results One cell line, which we called B6BC, fulfilled these criteria and allowed for the establishment of invasive estrogen receptor-positive (ER + ) tumors with features of epithelial to mesenchymal transition that were abundantly infiltrated by myeloid immune populations but scarcely by T lymphocytes, as determined by single-nucleus RNA sequencing and high-dimensional leukocyte profiling. Such tumors failed to respond to programmed cell death-1 (PD-1) blockade, but reduced their growth on treatment with ER antagonists, as well as with anthracycline-based chemotherapy, which was not influenced by T-cell depletion. Moreover, B6BC-derived tumors reduced their growth on CD11b blockade, indicating tumor sustainment by myeloid cells. The immune environment and treatment responses recapitulated by B6BC-derived tumors diverged from those of ER + TS/A cell-derived tumors in BALB/C mice, and of ER – E0771 cell-derived and MPA/DMBA-induced tumors in C57BL/6 mice. Conclusions B6BC is the first transplantable HR + BC cell line derived from C57BL/6 mice and B6BC-derived tumors recapitulate the complex tumor microenvironment of locally advanced HR + BC naturally resistant to PD-1 immunotherapy.
Tumor and local lymphoid tissue interaction determines prognosis in high-grade serous ovarian cancer
Authors: Haonan Lu, Hantao Lou, Georg Wengert, Reema Paudel, Naina Patel, Saral Desai, Bill Crum, Kristofer Linton-Reid, Mitchell Chen, Dongyang Li, Jacey Ip, Francesco Mauri, David J. Pinato, Andrea Rockall, Susan J. Copley, Sadaf Ghaem-Maghami, Eric O. Aboagye
Journal: Cell Reports Medicine (2023)

Tertiary lymphoid structure (TLS) is associated with prognosis in copy-number-driven tumors, including high-grade serous ovarian cancer (HGSOC), although the function of TLS and its interaction with copy-number alterations in HGSOC are not fully understood. In the current study, we confirm that TLS-high HGSOC patients show significantly better progression-free survival (PFS). We show that the presence of TLS in HGSOC tumors is associated with B cell maturation and cytotoxic tumor-specific T cell activation and proliferation. In addition, the copy-number loss of IL15 and CXCL10 may limit TLS formation in HGSOC; a list of genes that may dysregulate TLS function is also proposed. Last, a radiomics-based signature is developed to predict the presence of TLS, which independently predicts PFS in both HGSOC patients and immune checkpoint inhibitor (ICI)-treated non-small cell lung cancer (NSCLC) patients. Overall, we reveal that TLS coordinates intratumoral B cell and T cell response to HGSOC tumor, while the cancer genome evolves to counteract TLS formation and function.
Association between early suicidal trajectories in first-episode psychosis and 10-year follow-up: TIPS registry-linked study
Authors: Sherif M Gohar, Wenche ten Velden Hegelstad, Bjørn Auestad, Ulrik Helt Haahr, Inge Joa, Jan Olav Johannessen, Tor Ketil Larsen, Stein Opjordsmoen, Bjørn Rishovd Rund, Jan Ivar Røssberg, Erik Simonsen, Svein Friis, Ingrid Melle
Journal: The Lancet Psychiatry (2023)
Deep-learning-enabled brain hemodynamic mapping using resting-state fMRI
Authors: Xirui Hou, Pengfei Guo, Puyang Wang, Peiying Liu, Doris D. M. Lin, Hongli Fan, Yang Li, Zhiliang Wei, Zixuan Lin, Dengrong Jiang, Jin Jin, Catherine Kelly, Jay J. Pillai, Judy Huang, Marco C. Pinho, Binu P. Thomas, Babu G. Welch, Denise C. Park, Vishal M. Patel, Argye E. Hillis, Hanzhang Lu
Journal: npj Digital Medicine (2023)

Cerebrovascular disease is a leading cause of death globally. Prevention and early intervention are known to be the most effective forms of its management. Non-invasive imaging methods hold great promises for early stratification, but at present lack the sensitivity for personalized prognosis. Resting-state functional magnetic resonance imaging (rs-fMRI), a powerful tool previously used for mapping neural activity, is available in most hospitals. Here we show that rs-fMRI can be used to map cerebral hemodynamic function and delineate impairment. By exploiting time variations in breathing pattern during rs-fMRI, deep learning enables reproducible mapping of cerebrovascular reactivity (CVR) and bolus arrive time (BAT) of the human brain using resting-state CO2 fluctuations as a natural 'contrast media'. The deep-learning network was trained with CVR and BAT maps obtained with a reference method of CO2-inhalation MRI, which included data from young and older healthy subjects and patients with Moyamoya disease and brain tumors. We demonstrate the performance of deep-learning cerebrovascular mapping in the detection of vascular abnormalities, evaluation of revascularization effects, and vascular alterations in normal aging. In addition, cerebrovascular maps obtained with the proposed method exhibited excellent reproducibility in both healthy volunteers and stroke patients. Deep-learning resting-state vascular imaging has the potential to become a useful tool in clinical cerebrovascular imaging.
G-CSF rescue of FOLFIRINOX-induced neutropenia leads to systemic immune suppression in mice and humans
Authors: Victoire Cardot-Ruffino, Naima Bollenrucher, Luisa Delius, S Jennifer Wang, Lauren K Brais, Joshua Remland, C Elizabeth Keheler, Keri M Sullivan, Thomas A Abrams, Leah H Biller, Peter C Enzinger, Nadine J McCleary, Anuj K Patel, Douglas A Rubinson, Benjamin Schlechter, Sarah Slater, Matthew B Yurgelun, James M Cleary, Kimberly Perez, Michael Dougan, Kimmie Ng, Brian M Wolpin, Harshabad Singh, Stephanie K Dougan
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Recombinant granulocyte colony-stimulating factor (G-CSF) is routinely administered for prophylaxis or treatment of chemotherapy-induced neutropenia. Chronic myelopoiesis and granulopoiesis in patients with cancer has been shown to induce immature monocytes and neutrophils that contribute to both systemic and local immunosuppression in the tumor microenvironment. The effect of recombinant G-CSF (pegfilgrastim or filgrastim) on the production of myeloid-derived suppressive cells is unknown. Here we examined patients with pancreatic cancer, a disease known to induce myeloid-derived suppressor cells (MDSCs), and for which pegfilgrastim is routinely administered concurrently with FOLFIRINOX but not with gemcitabine-based chemotherapy regimens. Methods Serial blood was collected from patients with pancreatic ductal adenocarcinoma newly starting on FOLFIRINOX or gemcitabine/n(ab)paclitaxel combination chemotherapy regimens. Neutrophil and monocyte frequencies were determined by flow cytometry from whole blood and peripheral blood mononuclear cell fractions. Serum cytokines were evaluated pretreatment and on-treatment. Patient serum was used in vitro to differentiate healthy donor monocytes to MDSCs as measured by downregulation of major histocompatibility complex II (HLA-DR) and the ability to suppress T-cell proliferation in vitro. C57BL/6 female mice with pancreatic tumors were treated with FOLFIRINOX with or without recombinant G-CSF to directly assess the role of G-CSF on induction of immunosuppressive neutrophils. Results Patients receiving FOLFIRINOX with pegfilgrastim had increased serum G-CSF that correlated with an induction of granulocytic MDSCs. This increase was not observed in patients receiving gemcitabine/n(ab)paclitaxel without pegfilgrastim. Interleukin-18 also significantly increased in serum on FOLFIRINOX treatment. Patient serum could induce MDSCs as determined by in vitro functional assays, and this suppressive effect increased with on-treatment serum. Induction of MDSCs in vitro could be recapitulated by addition of recombinant G-CSF to healthy serum, indicating that G-CSF is sufficient for MDSC differentiation. In mice, neutrophils isolated from spleen of G-CSF-treated mice were significantly more capable of suppressing T-cell proliferation. Conclusions Pegfilgrastim use contributes to immune suppression in both humans and mice with pancreatic cancer. These results suggest that use of recombinant G-CSF as supportive care, while critically important for mitigating neutropenia, may complicate efforts to induce antitumor immunity.
Erratum to ‘Next-generation sequencing analysis of hepatitis C virus resistance–associated substitutions in directacting antiviral failure in South Korea’ [Clin Mol Hepatol 2023;29:496-509]
Authors: Kyung-Ah Kim, Sejoon Lee, Hye Jung Park, Eun Sun Jang, Youn Jae Lee, Sung Bum Cho, Young Seok Kim, In Hee Kim, Byung Seok Lee, Woo Jin Chung, Sang Hoon Ahn, Seungtaek Kim, Sook Hyang Jeong
Journal: Clinical and Molecular Hepatology (2023)
Effects of Cyanobacterial Harmful Algal Bloom Toxin Microcystin-LR on Gonadotropin-Dependent Ovarian Follicle Maturation and Ovulation in Mice
Authors: Yingzheng Wang, Pawat Pattarawat, Jiyang Zhang, Eunchong Kim, Delong Zhang, Mingzhu Fang, Elizabeth A. Jannaman, Ye Yuan, Saurabh Chatterjee, Ji-Yong Julie Kim, Geoffrey I. Scott, Qiang Zhang, Shuo Xiao
Journal: Environmental Health Perspectives (2023)

Cyanobacterial harmful algal blooms (CyanoHABs) originate from the excessive growth or bloom of cyanobacteria often referred to as blue-green algae. They have been on the rise globally in both marine and freshwaters in recently years with increasing frequency and severity owing to the rising temperature associated with climate change and increasing anthropogenic eutrophication from agricultural runoff and urbanization. Humans are at a great risk of exposure to toxins released from CyanoHABs through drinking water, food, and recreational activities, making CyanoHAB toxins a new class of contaminants of emerging concern.
Desmopressin for patients with spontaneous intracerebral haemorrhage taking antiplatelet drugs (DASH): a UK-based, phase 2, randomised, placebo-controlled, multicentre feasibility trial
Authors: Michael J R Desborough, Rustam Al-Shahi Salman, Simon J Stanworth, Diane Havard, Lisa J Woodhouse, Jennifer Craig, Kailash Krishnan, Paul M Brennan, Robert A Dineen, Tim J Coats, Trish Hepburn, Philip M Bath, Nikola Sprigg, Adrian Blight, Rahulan Dharmarajah, Alexander Dyker, Timothy England, German Guzman Gutierrez, Martin James, Amit Mistry, Neshika Samarasekera, Jane Sword, David Werring
Journal: The Lancet Neurology (2023)

The risk of death from spontaneous intracerebral haemorrhage is increased for people taking antiplatelet drugs. We aimed to assess the feasibility of randomising patients on antiplatelet drug therapy with spontaneous intracerebral haemorrhage to desmopressin or placebo to reduce the antiplatelet drug effect.
High-dose dual-antibiotic loaded cement for hip hemiarthroplasty in the UK (WHiTE 8): a randomised controlled trial
Authors: Nickil R Agni, Matthew L Costa, Juul Achten, Nicholas Peckham, Susan J Dutton, May Ee Png, Mike R Reed
Journal: The Lancet (2023)

Hip fracture is the most common injury requiring treatment in hospital. Controversy exists regarding the use of antibiotic loaded bone cement in hip fractures treated with hemiarthroplasty. We aimed to compare the rate of deep surgical site infection in patients receiving high-dose dual-antibiotic loaded cement versus standard care single-antibiotic loaded cement.We included people aged 60 years and older with a hip fracture attending 26 UK hospitals in this randomised superiority trial. Participants undergoing cemented hemiarthroplasty were randomly allocated in a 1:1 ratio to either a standard care single-antibiotic loaded cement or high-dose dual-antibiotic loaded cement. Participants and outcome assessors were masked to the treatment allocation. The primary outcome was deep surgical site infection at 90 days post-randomisation as defined by the US Centers for Disease Control and Prevention in an as-randomised population of consenting participants with available data at 120 days. Secondary outcomes were quality of life, mortality, antibiotic use, mobility, and residential status at day 120. The trial is registered with ISRCTN15606075.Between Aug 17, 2018, and Aug 5, 2021, 4936 participants were randomly assigned to either standard care single-antibiotic loaded cement (2453 participants) or high-dose dual-antibiotic loaded cement (2483 participants). 38 (1·7%) of 2183 participants with follow-up data in the single-antibiotic loaded cement group had a deep surgical site infection by 90 days post-randomisation, as did 27 (1·2%) of 2214 participants in the high-dose dual-antibiotic loaded cement group (adjusted odds ratio 1·43; 95% CI 0·87-2·35; p=0·16).In this trial, the use of high-dose dual-antibiotic loaded cement did not reduce the rate of deep surgical site deep infection among people aged 60 years or older receiving a hemiarthroplasty for intracapsular fracture of the hip.Heraeus Medical. Supported by the UK National Institute for Health and Care Research Oxford Biomedical Research Centre.
Mortality, Outcomes, Costs, and Use of Medicines Following a First Heart Failure Hospitalization
Authors: Biykem Bozkurt, Gianluigi Savarese, Samuel Adamsson Eryd, Johan Bodegård, John G.F. Cleland, Cindy Khordoc, Takuya Kishi, Marcus Thuresson, Orly Vardeny, Ruiqi Zhang, Lars H. Lund
Journal: JACC Heart Failure (2023)

There are few contemporary data on outcomes, costs, and treatment following a hospitalization for heart failure (hHF) in epidemiologically representative cohorts.This study sought to describe rehospitalizations, hospitalization costs, use of guideline-directed medical therapy (GDMT) (renin-angiotensin system inhibitors, sacubitril/valsartan, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors), and mortality after hHF.EVOLUTION HF (Utilization of Dapagliflozin and Other Guideline Directed Medical Therapies in Heart Failure Patients: A Multinational Observational Study Based on Secondary Data) is an observational, longitudinal cohort study using data from electronic health records or claims data sources in Japan, Sweden, the United Kingdom, and the United States. Adults with a first hHF discharge between 2018 and 2022 were included. The 1-year event rates per 100 patient-years (ERs) for death and rehospitalizations (with a primary diagnosis of heart failure (HF), chronic kidney disease [CKD], myocardial infarction, stroke, or peripheral artery disease) were calculated. Hospital health care costs were cumulatively summarized. Cumulative GDMT use was assessed using Kaplan-Meier estimates.Of 263,525 patients, 28% died within the first year post-hHF (ER: 28.4 [95% CI: 27.0-29.9]). Rehospitalizations were mainly driven by HF (ER: 13.6 [95% CI: 9.8-17.4]) and CKD (ER: 4.5 [95% CI: 3.6-5.3]), whereas the ERs for myocardial infarction, stroke, and peripheral artery disease were lower. Health care costs were predominantly driven by HF and CKD. Between 2020 and 2022, use of renin-angiotensin system inhibitors, sacubitril/valsartan, beta-blockers, and mineralocorticoid receptor antagonists changed little, whereas uptake of sodium-glucose cotransporter-2 inhibitors increased 2- to 7-fold.Incident post-hHF rehospitalization risks and costs were high, and GDMT use changed little in the year following discharge, highlighting the need to consider earlier and greater implementation of GDMT to manage risks and reduce costs.
Association between maternal benzodiazepine or Z-hypnotic use in early pregnancy and the risk of stillbirth, preterm birth, and small for gestational age: a nationwide, population-based cohort study in Taiwan
Authors: Lin-Chieh Meng, Chih-Wan Lin, Yi-Chin Lin, Shih-Tsung Huang, Yi-Yung Chen, Chi-Yung Shang, Chia-Yi Wu, Liang-Kung Chen, K Arnold Chan, Fei-Yuan Hsiao
Journal: The Lancet Psychiatry (2023)
Palliative care to support the needs of adults with neurological disease
Authors: Benzi M Kluger, Peter Hudson, Laura C Hanson, Radka Bužgovà, Claire J Creutzfeldt, Roop Gursahani, Malenna Sumrall, Charles White, David J Oliver, Steven Z Pantilat, Janis Miyasaki
Journal: The Lancet Neurology (2023)